Dexamethasone induces p21^cip1/waf1 expression via FoxO3a independently of the Lamin A/C-HDAC2 interaction in Ataxia Telangiectasia

Ataxia-Telangiectasia (A-T) is a very rare autosomal recessive multisystemic disorder which to date is still uncurable. The use of glucocorticoid analogs, such as dexamethasone (dex), can improve neurological symptoms in patients, but the molecular mechanism of action of these analogs remains unclear. Here, we report the effects of dex in regulating the interaction between Lamin A/C and HDAC2 in WT and A-T cells. Upon administration of dex to A-T cells, we first observed that the accumulation of HDAC2 on the CDKN1A promoter did not exert a repressive role on p21(cip1/waf1) expression, and second, we established that HDAC2 accumulation was not dependent on Lamin A/C. Both of these results are contrary to previous reported outcomes in other cellular models. Furthermore, large amounts of LAP2a and FoxO3a were found to occupy the CDKN1A promoter with matched p21(cip1/waf1) overexpression. Hence, in A-T cells p21 could be activated as a result of a dex-induced rearrangement of a multicomponent complex, composed of Lamin A/C, HDAC2, LAP2a, pRb, E2F1, and FoxO3a, at the CDKN1A gene promoter.